tbuckley/cabot-search huggingface dataset:
Abstract 2905: A novel therapeutic antibody against CD73 that ameliorates the tumor microenvironment and improves the efficacy of cancer immunotherapy
Authors: Noriko Matsumoto, Yuji Mishima, Toshifumi Obonai, Haruka Ban, Motoya Mie, Norihiro Nakamura
Journal: Cancer Research (2022)

Abstract Background: CD73, also known as ecto-5’-nucleotidase (NT5E), is a GPI-anchored cell surface enzyme expressed on certain types of immune cells and tumor cells. This enzyme catalyzes the hydrolytic conversion of extracellular adenosine monophosphate (AMP) to adenosine (Ado) that suppresses tumor-infiltrating immune cells via the adenosine receptors, allowing tumors to escape the immune system. Here, we introduce a novel anti-human CD73 antibody called BP1200 that strongly blocks the generation of Ado by CD73 and thereby reverses immune suppression in tumors. Methods: We screened anti-CD73 antibodies by antigen-specific single B cell sorting from mice immunized with recombinant human CD73. CDRs of the antibodies that inhibit the enzyme activity of CD73 were engrafted into human IgG1 framework carrying the mutations of Fc silent. The proliferation and cytotoxicity of T cells were analyzed using human peripheral blood mononuclear cells (PBMC) in the presence of ATP. Efficacy of BP1200 in vivo was investigated by using mice bearing human CD73 knock-in-MC38 cells and mice implanted with human NSCLC cell line (NCI-H292) and PBMC. Results: The humanized anti-CD73 antibody (BP1200) binds to both human and cynomolgus CD73 expressed on cell surface with KD value of 0.2 nM (human CD73). BP1200 blocked the hydrolysis of AMP by CD73 expressed as both membrane-bound and soluble form without the hook effect. BP1200 induced internalization of CD73 and remarkably decreased the cell surface CD73, indicating that BP1200 inhibits the enzyme activity as well as downregulates the protein level of CD73 at the cell surface. BP1200 induced in vitro proliferation, cytokine production, and cytotoxic activity of T cells even in the presence of high level of ATP, suggesting that BP1200 enhances the T cell immunity in immunosuppressive tumor micro-envelopment (TME). In vivo studies showed that the combination treatment of BP1200 with anti-PD-1/PD-L1 antibodies remarkably retarded tumor growth. Moreover, the mice administrated with BP1200 and anti-PD-1 exhibited long-term immune memory effects that rendered them resistant to rechallenge with tumors. Conclusions: The novel anti-human CD73 antibody, BP1200, ameliorates immunosuppressive TME caused by adenosine and enhances antitumor immune responses. The combination of BP1200 and immune-checkpoint inhibitors for cancer treatment will be a promising therapeutic option in clinical practice. Citation Format: Noriko Matsumoto, Yuji Mishima, Toshifumi Obonai, Haruka Ban, Motoya Mie, Norihiro Nakamura. A novel therapeutic antibody against CD73 that ameliorates the tumor microenvironment and improves the efficacy of cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2905.
Abstract 2294: Genomic landscape and immunological profile of glioblastoma in East Asians
Authors: Davy Deng
Journal: Cancer Research (2022)

Abstract While it is well known that Glioblastoma (GBM) shows profound inter- and intra-tumoral heterogeneity, the ancestry disparities among races have been largely overlooked. By comparing the predominantly caucasian TCGA GBM dataset (EUR, n=383) with a large genomic and transcriptomic East Asian GBM dataset (EAS, n=443), we identified numerous significant differences between EAS-GBM and EUR-GBM. Transcriptomic clustering also established a novel EAS-GBM molecular classification system and the discovery of a new EAS-specific GBM subtype. We characterized each subtype comprehensively including genomic alterations, immune profile and TCR/BCR repertoire analysis. This study elucidates important ancestry-dependent biological and molecular differences between GBMs and proposes a new transcriptome-based EAS-GBM classification. Understanding these unique features contribute to a more comprehensive characterization of the heterogeneity in GBM patients and could facilitate more careful patient stratification during targeted therapy and drug development. Citation Format: Davy Deng. Genomic landscape and immunological profile of glioblastoma in East Asians [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2294.
Abstract 5919: Regulation of SLPI secretion by NFX1-123 and HPV 16 E6 in cervical cancer
Authors: Sreenivasulu Chintala, Kevin Quist, Rachel Katzenellenbogen
Journal: Cancer Research (2022)

Abstract Background: Secretory Leukocyte Peptidase Inhibitor (SLPI) functions in cancer progression, cellular invasion, metastasis, immune evasion, and chemoresistance. Our previous studies showed increased SLPI with overexpressed NFX1-123 and co-expressed high-risk (HR) human papillomavirus type 16 E6 oncogene (16E6) in primary keratinocytes (HFKs) as well as high SPLI levels in cervical cancers. The HR viral oncogenes E6 and E7 partner with host cell proteins to regulate cell cycle regulation and immortalization pathways. Understanding the mechanisms of SLPI upregulation in HPV-associated cancers is critical to validating SLPI as a non-invasive biomarker as well as to test its utility in future cancer treatments. This study was designed to quantify intracellular and secreted SLPI protein in cervical cancer and to determine the roles NFX1-123 and 16E6 have on SLPI expression and secretion. Methods: Using HPV- and HPV+ cervical cancer cell lines and HFKs transduced with overexpressed NFX1-123 and 16E6, or vector controls, we measured intracellular and secreted SLPI by Western blot and ELISA, respectively. In HPV+ cervical cancer cell lines, NFX1-123 was knocked down or out by shRNA or CRISPR-Cas9, respectively, and 16E6 and 16E7 were knocked down by siRNA. In those cells, intracellular and secreted SLPI was quantified and the relative role of NFX1-123, 16E6, and 16E7 were studied. Selected classical and non-classical secretory pathways markers were also measured to assess their effects on SLPI secretion. Finally, SLPI’s concentration was measured by ELISA in cervical cancer patient sera and compared to healthy controls. Results: Our results showed increased intracellular as well as secreted SLPI in HFKs with overexpressed NFX1-123 and 16E6. Similarly, we found increased SLPI secretion in HPV+ cervical cancer cell lines (SiHa, Caski and HeLa) when compared to HPV- C33A cells. A reduction in NFX1-123 and 16E6 led to decreased SLPI secretion, pointing to a regulation of SLPI by NFX1-123 and 16E6 on SLPI secretion. Analysis of classical and non-classical secretory pathway markers suggested that NFX1-123 regulated non-classical pathways, which may drive greater secretion of SLPI in HPV+ cervical cancers. Higher SLPI protein amounts were found cervical cancer patient sera when compared to healthy controls. Conclusions: Our results suggest a functional role for NFX1-123 and 16E6 in SLPI secretion in cervical cancer and that SLPI may be a potential biomarker in cervical cancer. Citation Format: Sreenivasulu Chintala, Kevin Quist, Rachel Katzenellenbogen. Regulation of SLPI secretion by NFX1-123 and HPV 16 E6 in cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5919.
Abstract 982: A new transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma
Authors: Adele Mirna Alchahin, Shenglin Mei, Ioanna Tsea, Taghreed Hirz, Youmna Kfoury, Douglas Dahl, Chin-Lee Wu, Alexander O. Subtelny, Shulin WU, David T. Scadden, John H. Shin, Philip J. Saylor, David B. Sykes, Peter V. Kharchenko, Ninib Baryawno
Journal: Cancer Research (2022)

Abstract Introduction: Renal cell carcinoma, particularly the clear cell histological subtype (ccRCC), is the most common kidney cancer in adults, accounting for 75-85% of all cases. When it is localized to the kidney, it is often cured with surgical resection or thermal ablation. One quarter of the patients have evidence of metastatic disease at the time of diagnosis, and in this setting ccRCC still is a highly lethal disease with few effective treatment options. In this study we used single-cell RNA-sequencing to characterize tumor cell clonality, metastatic signatures and the tumor microenvironment in ccRCC at the single-cell level. Methodological approach: Here we took advantage of fresh patient samples that included treatment-naive primary tumor tissue, matched adjacent normal kidney tissue, as well as tumor samples collected from patients with bone metastases. We used single cell RNA sequencing (10X Genomics, Chromium 3’ v2 kit, 10x Genomics), that was analyzed with PAGODA and CONOS. Summary of new unpublished data: Our analysis revealed a distinct transcriptional signature that predicts metastatic potential and patient survival was disclosed through the single-cell analysis. In-depth exploration of the supporting stromal cells displayed a phenotype of vascular remodeling within the endothelial cells. The fibroblasts showed a proliferative signature that was associated with poor survival. An in silico cell-to-cell interaction analysis highlighted the CXCL9/CXCL10-CXCR3 axis and the CD70-CD27 axis as potential therapeutic targets. Conclusions: Our discoveries in ccRCC provide complementary biological insights, specifically in the interplay between tumor cells and their microenvironment in ccRCC. We demonstrate important biological insights into ccRCC biology including: (1) identification of a distinct metastatic signature that predicts survival outcome, (2) discovery of a proximal tubule cell population that may represent the ccRCC cell of origin, and (3) a detailed exploration in the immunosuppressive environment and the stromal alterations in treatment-naïve patients. In addition, we stress potential therapeutic targets for further evaluation in preclinical models. Citation Format: Adele Mirna Alchahin, Shenglin Mei, Ioanna Tsea, Taghreed Hirz, Youmna Kfoury, Douglas Dahl, Chin-Lee Wu, Alexander O. Subtelny, Shulin WU, David T. Scadden, John H. Shin, Philip J. Saylor, David B. Sykes, Peter V. Kharchenko, Ninib Baryawno. A new transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 982.
<i>hapln1</i> Defines an Epicardial Cell Subpopulation Required for Cardiomyocyte Expansion During Heart Morphogenesis and Regeneration
Authors: Jisheng Sun, Elizabeth A. Peterson, Annabel Z. Wang, Jianhong Ou, Kieko E. Smith, Kenneth D. Poss, Jinhu Wang
Journal: Circulation (2022)

Background: Certain nonmammalian species such as zebrafish have an elevated capacity for innate heart regeneration. Understanding how heart regeneration occurs in these contexts can help illuminate cellular and molecular events that can be targets for heart failure prevention or treatment. The epicardium, a mesothelial tissue layer that encompasses the heart, is a dynamic structure that is essential for cardiac regeneration in zebrafish. The extent to which different cell subpopulations or states facilitate heart regeneration requires research attention. Methods: To dissect epicardial cell states and associated proregenerative functions, we performed single-cell RNA sequencing and identified 7 epicardial cell clusters in adult zebrafish, 3 of which displayed enhanced cell numbers during regeneration. We identified paralogs of hapln1 as factors associated with the extracellular matrix and largely expressed in cluster 1. We assessed HAPLN1 expression in published single-cell RNA sequencing data sets from different stages and injury states of murine and human hearts, and we performed molecular genetics to determine the requirements for hapln1 -expressing cells and functions of each hapln1 paralog. Results: A particular cluster of epicardial cells had the strongest association with regeneration and was marked by expression of hapln1a and hapln1b . The hapln1 paralogs are expressed in epicardial cells that enclose dedifferentiated and proliferating cardiomyocytes during regeneration. Induced genetic depletion of hapln1 -expressing cells or genetic inactivation of hapln1b altered deposition of the key extracellular matrix component hyaluronic acid, disrupted cardiomyocyte proliferation, and inhibited heart regeneration. We also found that hapln1 -expressing epicardial cells first emerge at the juvenile stage, when they associate with and are required for focused cardiomyocyte expansion events that direct maturation of the ventricular wall. Conclusions: Our findings identify a subset of epicardial cells that emerge in postembryonic zebrafish and sponsor regions of active cardiomyogenesis during cardiac growth and regeneration. We provide evidence that, as the heart achieves its mature structure, these cells facilitate hyaluronic acid deposition to support formation of the compact muscle layer of the ventricle. They are also required, along with the function of hapln1b paralog, in the production and organization of hyaluronic acid–containing matrix in cardiac injury sites, enabling normal cardiomyocyte proliferation and muscle regeneration.
Abstract 1339: Interleukin 4 Producing CD4 T cells initiate a crucial event for lung cancer development
Authors: Gajendra Jogdand, Sayantan Banerjee, Gongping Shi, Jami Willet Brown, Amit Singh, Yongmei Zhao, Jyoti Shetty, Bao Tran, Yinling Hu
Journal: Cancer Research (2022)

Abstract Lung cancer remains one of the leading causes of mortality of cancer patients. Kinase-dead Ikkα knock-in (KA/KA) mice develop CD4 T cell-derived autoimmune disease. Previously, we reported spontaneous lung squamous cell carcinoma (SCC) associated with increase macrophage and CD4 T cell numbers in KA/KA mice. Depleting macrophages dampens lung SCC development in KA/KA mice, but a lot of CD4 T cells remain in the lungs. The activity of CD4 T cells in lung SCC development is unknown. In this study, we attempted to investigate the role of CD4 T cells in lung SCC development. We performed adoptive CD4 T cell transfer experiment and found that KA/KA CD4 T cell transfer, not WT CD4 T cells, recruited marked macrophages to the lungs and induced lung SCC in KA/KA;Rag1-/- mice. The CD4 T cells isolated from the lungs of KA/KA mice and KA/KA;Rag1-/- mice with KA/KA CD4 T cell transfer expressed elevated PD-1, IL-4, IL-5, Il-13, and Il-21 levels compared to WT mice. We found that Il4 ablation, not Il5 deletion, reduced macrophage recruitment and blocked SCC development in KA/KA;Il4-/- mice as well as unlike KA/KA CD4 T cells, KA/KA;Il4-/- CD4 T cells did not induce spontaneous lung SCC in KA/KA;Rag1-/- mice with KA/KA;Il4-/- CD4 T cell injections. Taken together, the finding highlights a pathogenic role of IL-4-producing CD4 T cells in lung carcinogenesis. Citation Format: Gajendra Jogdand, Sayantan Banerjee, Gongping Shi, Jami Willet Brown, Amit Singh, Yongmei Zhao, Jyoti Shetty, Bao Tran, Yinling Hu. Interleukin 4 Producing CD4 T cells initiate a crucial event for lung cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1339.
Abstract 2235: Identifying populations at elevated risk of cancer outside those traditionally targeted for screening and prevention
Authors: Alpa V. Patel, Emily Deubler, Lauren R. Teras, Graham A. Colditz, Cari J. Lichtman, William G. Cance, Christina A. Clarke
Journal: Cancer Research (2022)

Introduction: Currently, populations are identified for cancer screening interventions one cancer type at a time. With new developments in cancer screening, including multi-cancer early detection tests, it is important and timely to understand the overall cancer burden in populations outside those traditionally targeted for single-cancer screenings. Thus, we sought to identify the most important risk factors for developing any invasive cancer, and to calculate associated 5-year absolute risks, with a particular focus on persons under age 50 years.Methods: Two large American Cancer Society cohorts followed prospectively for cancer, the Cancer Prevention Study-II Nutrition Cohort (CPS-IINC) enrolled from 1992-1993 and Cancer Prevention Study 3 (CPS-3) enrolled from 2006-2013, were used to examine a broad range of cancer risk factors. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for associations between potential risk factors and subsequent overall risk of any invasive cancer. The Individualized Coherent Absolute Risk Estimation tool used these HRs to estimate absolute risk in 5-year age groups.Results: 15,226 cancers were identified among 429,991 participants within 5 years of follow-up. Several risk factors including smoking history, obesity, alcohol, family history of cancer, and various chronic medical conditions (e.g., diabetes, hypertension) were associated with a higher risk of cancer. Persons above age 50 years, regardless of other risk factors considered, had at least 2% absolute risk per 5 years. Among persons under age 50 years, smoking status was the most important factor differentiating risk. For men under age 50, absolute risk of any cancer did not exceed 2% except for men ages 45-49 years who currently smoke or recently quit (within 30 years). For women under age 50, absolute risk exceeded 2% starting at age 35-39 years for current or recent former smokers, and all women, even long-term nonsmokers, at age 45-49 had over 2% absolute risk.Conclusions: Smoking history is important in differentiating absolute risk of any cancer in adults under age 50 years. More research to understand the extent to which other cancer risk factors influence risk for specific populations aged <50 years should be carried out.Citation Format: Alpa V. Patel, Emily Deubler, Lauren R. Teras, Graham A. Colditz, Cari J. Lichtman, William G. Cance, Christina A. Clarke. Identifying populations at elevated risk of cancer outside those traditionally targeted for screening and prevention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2235.
Abstract 4145: Novel approach that combines an automated breast cancer grading platform with genomics to personalize risk assessment and management
Authors: Michael J. Donovan
Journal: Cancer Research (2022)

Abstract Background: The role of histopathology including stage, tumor size and histologic grade in defining breast cancer (BCA) clinical risk assignment continues to be an important component of treatment choice and management. Recent publications have demonstrated the significance of combining these features with genomic signatures such as Oncotype and EndoPredict to provide precision risk assessment. Unfortunately, intra-inter pathologist BCA grading variability remains a significant limiting factor. Methods: Using the Cancer Genome Atlas (TCGA) breast cancer (BCA) image dataset, clinical and genomic data (i.e., EndoPredict and Oncotype), we evaluated a series of H&amp;E images from patients with infiltrating ductal BCA (one slide per patient). A machine-learning (ML) derived morphology feature array was used to normalize staining differences, identify regions of tumor vs. normal and characterize individual cellular attributes including tubule structure and organization, nuclear morphology, and mitotic figures. Individual features were correlated with overall survival using the concordance index (c-index), support vector models and Kaplan-Meier incidence curves to understand feature importance. Results: ML curated image features representing BCA gland morphology were generated from 517 patients with 69 events (13%), 93% overall survival (OS), median 5-years. Three clinical variables including: age, 59 years (median), AJCC stage T2 and 49% grade 3 and 41% grade 2, along with results of the EndoPredict (EP) and an Onctoype (ONC) gene subset: PGR, ESR1, CCNB1, BIRC5, MYBL2, GRB7) and imaging features were evaluated. Only age, stage and 10 imaging features representing nuclear shape, size, mitotic activity, lymphoid aggregates and stromal content were selected. Two models consisting of clinical + gene expression + imaging produced a C-index of: 0.84 (EP) vs. 0.82 (ONC), respectively, vs. clinical (0.79) and clinical + genomics ( EP 0.81vs. ONC 0.79). Conclusions: A machine-learning platform outperformed grade and produced accurate recurrence risk models with demonstrated added improvement over clinical and genomic analyses. Future studies include expanded cohort studies to confirm and expand these observations. Citation Format: Michael J. Donovan. Novel approach that combines an automated breast cancer grading platform with genomics to personalize risk assessment and management [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4145.
Abstract 6073: First-in-class Doublecortin-like kinase 1 (DCLK1) inhibitor for targeting cancer stem cell in hepatocellular carcinoma
Authors: Daseul Yoon, Seung Hee Jung, Ju Young Jang, Ji-Young Ahn, Seung Jin Jo, Donghyun Ko, Dong-kyu Kim, Su Jong Yu
Journal: Cancer Research (2022)

Abstract Cancer stem cells (CSCs) have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. Doublecortin-like kinase 1 (DCLK1) was recently identified as CSC marker is upregulated in several solid tumors, which distinguishes between cancer and normal stem cell. However, the role of DCLK1 in hepatocellular carcinoma (HCC) is unclear. According to the open database like TCGA, overexpression of DCLK1 is reported to be associated with poor prognosis in HCC patients. It was also observed that DCLK1 expression was significantly increased in the advanced stage of HCC. In addition, as a result of measuring the serum DCLK1 levels obtained from patients with liver cirrhosis or HCC treated at Seoul National University Hospital, it was confirmed that the expression of DCLK1 was significantly increased in patients with HCC compared to those with liver cirrhosis. It was also confirmed that DCLK1 was expressed in human HCC cell lines and that the expression levels of DCLK1 mRNA and protein were further increased in CSC rich human HCC cell lines. Moreover, cell death was increased at the cellular level when DCLK1 was blocked via inhibiting expression of CSC markers such as CD133 and EpCAM. After evaluating the effect of DCLK1 inhibition in CSC rich human HCC cells lines, it was found that spheroid formation decreased by suppressing CSCs markers including LGR5 and CD133. In addition, it was confirmed that cell migration decreased when DCLK1 was blocked. Even in the murine HCC model, it was found that the antitumor effect was showed when administered with DCLK1 inhibitor, DCLK1-IN-1, in xenograft model with CSC rich HCC cell lines. Our results support that DCLK1 can be used as a biomarker for the detection of HCC and may be a candidate for developing targeted therapeutics to eradicate HCC. Citation Format: Daseul Yoon, Seung Hee Jung, Ju Young Jang, Ji-Young Ahn, Seung Jin Jo, Donghyun Ko, Dong-kyu Kim, Su Jong Yu. First-in-class Doublecortin-like kinase 1 (DCLK1) inhibitor for targeting cancer stem cell in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6073.